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Cell Growth Inhibition by Okadaic Acid Involves Gut-Enriched Kruppel-like Factor–Mediated Enhanced Expression of c-Myc

¹ John D. Dingell V.A. Medical Center and Departments of ² Internal Medicine and ³ Surgery and ⁴ Karmanos Cancer Institute, Wayne State University, Detroit, Michigan and ⁵ Department of Medicine, Yale University School of Medicine, New Haven, Connecticut

Requests for reprints: Arun K. Rishi, John D. Dingell VA Medical Center, Research 151, Room B 4270, 4646 John R., Detroit, MI 48201. Phone: 313-576-1000, ext. 4492; Fax: 313-576-1112; E-mail: Rishia{at}Karmanos.org.

Human breast cancer (HBC) cell growth suppression by okadaic acid (OA) was previously found to involve elevated expression of oncogenes c-myc and c-fos and apoptosis. Since, c-Myc influences diverse pathways of cell growth, we hypothesized that elevated levels of c-Myc are involved in HBC growth suppression. Here, we investigated whether induction of c-Myc by OA or protein synthesis inhibitor cycloheximide contributed to HBC growth inhibition and the mechanisms involved. OA, cycloheximide, or the chemotherapeutic drug Taxol suppressed HBC cell growth. However, OA or cycloheximide treatments over 6 or 10 h, respectively, induced c-Myc expression. Depletion of c-Myc, on the other hand, resulted in enhanced HBC cell viabilities when exposed to OA or cycloheximide, but not by Taxol. OA induced c-myc transcription by targeting an 80-bp region from positions –11 to +70, relative to the P1 transcription start of mouse c-myc promoter. Gel mobility shift assays revealed binding of HBC cell nuclear proteins to the OA-responsive c-myc promoter fragment, whereas binding of one complex was elevated in the case of the OA-treated or cycloheximide-treated HBC cell nuclear extracts. Database search revealed presence of a consensus sequence for zinc finger protein gut-enriched Kruppel-like factor (GKLF) in OA-responsive region of the c-myc promoter. Mutation of GKLF consensus sequences abrogated OA responsiveness of the c-myc promoter, and OA treatments caused enhanced expression of GKLF in HBC cells. Thus, OA-dependent attenuation of HBC growth is accomplished, in part, by zinc finger transcription factor GKLF-mediated enhanced transcription of c-myc. [Cancer Res 2007;67(21):10198–206]